Cytomegalovirus vectors enabling control of T cell targeting

Patent metadata

Field	Value
Publication number	US-10316334-B2
Application number	US-201715693558-A
Country	US
Kind code	B2
Filing date	Sep 1, 2017
Priority date	Mar 5, 2013
Publication date	Jun 11, 2019
Grant date	Jun 11, 2019

Abstract

CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL128 protein (or an ortholog thereof) but lacking an active UL130 protein (or an ortholog thereof) are provided. CMV vectors comprising a heterologous protein antigen, an active UL131 protein (or an ortholog thereof), and an active UL130 protein (or an ortholog thereof) but lacking an active UL128 protein are also provided. In addition, methods of using CMV vectors to generate an immune response characterized as having at least 10% of the CD8+ T cells directed against epitopes presented by MHC Class II are provided.

First claim

The invention claimed is:

1. A human or animal cytomegalovirus (CMV) vector comprising:
a first nucleic acid sequence that encodes a heterologous protein antigen; a second nucleic acid sequence that encodes UL128 or an ortholog thereof; and a third nucleic acid sequence that encodes UL131 or an ortholog thereof; wherein the vector does not express an active UL130 protein; or
(ii) a first nucleic acid sequence that encodes a heterologous protein antigen; a second nucleic acid sequence that encodes UL130 or an ortholog thereof; and a third nucleic acid sequence that encodes UL131 or an ortholog thereof; wherein the vector does not express an active UL128 protein.

2. The vector of claim 1 , wherein the vector comprises a mutation in UL128 or UL130 selected from a point mutation, a frameshift mutation, or a deletion of all or less than all of UL128 or UL130.

3. The vector of claim 1 , further comprising a fourth nucleic acid sequence which comprises an antisense sequence or an RNAi sequence that inhibits the expression of UL128 or UL130.

4. The vector of claim 1 , wherein the heterologous antigen comprises a pathogen specific antigen.

5. The vector of claim 4 , wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, herpes simplex virus type 1(HSV1), herpes simplex virus type 2 (HSV2), hepatitis B virus, human papillomavirus, or Mycobacterium tuberculosis.

6. A method of generating a CD8 + T cell response to a heterologous antigen in a subject, the method comprising administering to the subject an effective amount of a CMV vector according to claim 1 ; wherein at least 10% of the CD8+ T cells to the heterologous antigen are directed against epitopes presented by Major Histocompatibility Complexes (MHO Class II.

7. The method of claim 6 , wherein at least 50% of the CD8 + T cells to the heterologous antigen are directed against epitopes presented by MHC Class II.

8. The method of claim 7 , wherein the heterologous antigen comprises a pathogen specific antigen.

9. The method of claim 8 , wherein the pathogen specific antigen is derived from human immunodeficiency virus, simian immunodeficiency virus, herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), hepatitis B virus, human papillomavirus, or Mycobacterium tuberculosis.

10. The method of claim 6 , wherein the subject is a rhesus macaque that has been previously exposed to RhCMV, and wherein the CMV vector is an RhCMV vector.

11. The method of claim 6 , wherein the subject is a human that has been previously exposed to HCMV, and wherein the CMV vector is an attenuated HCMV vector.

12. The method of claim 6 , wherein the administering comprises intravenous, intramuscular, intraperitoneal, or oral administration.

13. The vector of claim 1 , wherein the heterologous antigen comprises a cancer antigen.

14. The vector of claim 13 , wherein the cancer antigen is a prostate cancer antigen.

15. The vector of claim 1 , wherein the CMV vector is an attenuated HCMV vector.

16. The vector of claim 1 , wherein the CMV vector is an RhCMV vector.

17. The method of claim 7 , wherein the heterologous antigen comprises a cancer antigen.

18. The method of claim 17 , wherein the cancer antigen is a prostate cancer antigen.

19. A method of generating a CD8 + T cell response to a pathogen specific antigen in a human subject that has been previously exposed to HCMV, the method comprising administering to the subject an effective amount of a HCMV vector comprising;
(i) a first nucleic acid sequence that encodes a pathogen specific antigen; a second nucleic acid sequence that encodes UL128 or an ortholog thereof and a third nucleic acid sequence that encodes UL131 or an ortholog thereof; wherein the vector does not express an active UL130 protein; or
(ii) a first nucleic acid sequence that encodes a pathogen specific antigen; a second nucleic acid sequence that encodes UL130 or an ortholog thereof and a third nucleic acid sequence that encodes UL131 or an ortholog thereof; wherein the vector does not express an active UL128 protein;

wherein at least 10% of the CD8+ T cells to the pathogen specific antigen are directed against epitopes presented by MHC Class II; and wherein the pathogen specific antigen is derived from herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), hepatitis B virus, Mycobacterium tuberculosis , or human papillomavirus.

20. The method of claim 19 , wherein at least 50% of the CD8 + T cells to the pathogen specific antigen are directed against epitopes presented by MEW Class II.

21. The method of claim 19 , wherein the administering comprises intravenous, intramuscular, intraperitoneal, or oral administration.

22. The vector of claim 1 , wherein the heterologous antigen comprises an antigen derived from Mycobacterium tuberculosis.

23. The method of claim 6 , wherein the heterologous antigen comprises an antigen derived from Mycobacterium tuberculosis.

Assignees

• Univ Oregon Health & Science

Inventors

• Picker Louis
• Hansen Scott
• Frueh Klaus
• Malouli Daniel

Classifications

• C12N2740/15034

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• C12N2710/16143

  viral genome or elements thereof as genetic vector · CPC title

• A61K2039/572

  cytotoxic response · CPC title

• A61K2039/5256

  expressing foreign proteins · CPC title

• A61K39/04

  Mycobacterium, e.g. Mycobacterium tuberculosis · CPC title